Effects of Selective Cyclooxygenase-2 and Nonselective Cyclooxygenase Inhibition on Myocardial Function and Perfusion

Abstract

Non-selective NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors are purported to increase adverse cardiovascular events. We hypothesized COX-2 inhibitors would alter myocardial blood flow, microvascular reactivity, oxidative stress, and prostaglandin levels. Adult Yorkshire swine were divided into three groups: no drug (control, n=7), a non-selective COX inhibitor (naproxen 400mg daily, NAP, n=7), or a selective COX-2 inhibitor (celecoxib 200mg daily, CBX, n=7). After 7 weeks physiologic measurements were taken and tissue harvested. Animals in the CBX group demonstrated significantly higher blood pressure and rate pressure product. The NAP and CBX groups demonstrated an increased microvascular contraction response to serotonin. The NAP group showed increased myocardial levels of thromboxane and lower levels of prostacyclin. Levels of protein oxidative stress were increased in the CBX group. Myocardial apoptosis was lowest in the NAP group. Immunoblotting demonstrated decreased VEGF and phospho-eNOS expression in the NAP and CBX groups. Myocardial TNFα was increased in both the NAP and CBX groups. Immunostaining for thromboxane A 2 synthase and receptor demonstrated expression within the vascular smooth muscle and no observable differences between groups. Non-selective and selective COX inhibition does not alter myocardial perfusion, but results in altered myocardial and vascular physiology that may have implications regarding cardiovascular risk.

Effects of cyclooxygenase inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia

“…Similar experiments by our lab on nonischemic myocardium and normocholesterolemic animals did not demonstrate such pronounced improvements in microvascular function with COX inhibition (21,22). The combination of hypercholesterolemia and chronic ischemia seems to create an environment that is particularly susceptible to the beneficial effects of COX-2 inhibition.…”

Parecoxib reduced ventilation induced lung injury in acute respiratory distress syndrome

“…MPO mediates peroxidation of chloride ions to form hypochlorous acid, which can directly damage lung epithelial and endothelial cells. MPO is also a significant source of tyrosine nitration, which can evoke protein conformational changes and damage to cell membranes [32, 33]. Evidence suggests that MPO promotes oxidation and nitrification during ischemia and reperfusion [34].…”

Histological changes caused by meclofenamic acid in androgen independent prostate cancer tumors: evaluation in a mouse model

“…Various NSAIDs can inhibit tumor growth by drastically reducing their vascularization ( 29 ). This effect is generated when endothelial cell apoptosis is induced ( 30 ), or through the reduction of vascular endothelial growth factor (VEGF) levels - one of the principal angiogenesis inducers ( 31 – 33 ). In addition it has been reported that AKR1C3 overexpression promotes angiogenesis and aggressiveness of PCa cells (PC3), suggesting that AKR1C3-inhibition would reduce angiogenesis.…”